Next Article in Journal
Serine/Threonine Protein Kinases as Attractive Targets for Anti-Cancer Drugs—An Innovative Approach to Ligand Tuning Using Combined Quantum Chemical Calculations, Molecular Docking, Molecular Dynamic Simulations, and Network-like Similarity Graphs
Next Article in Special Issue
Bismuth(III)-Catalyzed Regioselective Selenation of Indoles with Diaryl Diselenides: Synthesis of 3-Selanylindoles
Previous Article in Journal
The Significance of Lignocellulosic Raw Materials on the Pore Structure of Activated Carbons Prepared by Steam Activation
Previous Article in Special Issue
Synthesis of Thionated Perylenediimides: State of the Art and First Investigations of an Alternative to Lawesson’s Reagent
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 13
10.3390/molecules29133196
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Iron-Catalyzed Sulfonylmethylation of Imidazo[1,2-α]pyridines with N,N-Dimethylacetamide and Sodium Sulfinates

by
Shengnan Sun
,
Hexia Ye
,
Haibo Liu
*,
Junchen Li
* and
Xiaojing Bi
*
State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(13), 3196; https://doi.org/10.3390/molecules29133196
Submission received: 15 May 2024 / Revised: 17 June 2024 / Accepted: 18 June 2024 / Published: 5 July 2024
(This article belongs to the Special Issue Organosulfur and Organoselenium Chemistry)
Browse Figures
Versions Notes

Abstract

Functionalized imidazo[1,2-α]pyridines are important scaffolds in pharmaceuticals. Herein, we present an efficient 3-sulfonylmethylation protocol for imidazo[1,2-α]pyridines by sodium sulfinates in DMA and H2O (2:1) via an FeCl3-catalyzed three-component coupling reaction. Various sulfonylmethyl imidazo[1,2-α]pyridines were thus afforded in high yields with excellent functional group tolerance. A plausible oxidation-addition mechanism was proposed.

Graphical Abstract

1. Introduction

As a kind of privileged scaffold, imidazo[1,2-α]pyridines are often used as the pharmacodynamic backbones of versatile drugs, such as anti-ulcer [1], anti-inflammatory [2], anti-viral [3,4], anti-bacterial [5], anti-cancer [6], anti-HIV [7] and anti-tuberculosis pharmaceutical candidates [8]. Owing to the electron-rich nature of imidazo[1,2-α]pyridine, the functionalization of imidazo[1,2-α]pyridine, especially C3-positioned C-C and C-X (O/N/S) bond construction, has attracted widespread attention [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Nevertheless, imidazo[1,2-α]pyridines containing sulfur functionality, such as sulfonylmethylated imidazo[1,2-α]pyridines, have been rarely studied before, whilst the sulfones group exists widely in drug molecules. The first typical example reported by Song employed the iron-involved tosylmethylation of imidazo[1,2-α]pyridines with p-toluenesulfonyl methyl isocyanide in H2O and PEG400 [27]. Then, Rode described a selectfluor-mediated approach regarding the methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines using DMSO as the carbon insertion synthon [28]. A very recent study reported by Tang demonstrated another efficient protocol for the direct C-3 sulfonylmethylation of imidazo[1,2-α]pyridines with glyoxylic acid and sodium sulfinates in water [29]. Some studies that have used DMA as a carbon source have been reported for the coupling of C-C bonds [30,31,32]. However, a new methodology enabling the C-H sulfonylmethylation of imidazo[1,2-α]pyridines is still highly desirable and valuable.
In our previous work, sodium sulfinates were found to be an effective and universal sulfur source in eco-friendly S-S and S-C bond construction [33]. In our following explorations, the unexpected sulfonylmethylation of imidazo[1,2-α]pyridines was observed when researchers tried to synthesize sulfones in DMA. Herein, we wish to present a new method for the iron-catalyzed sulfonylmethylation of imidazo[1,2-α]pyridines with DMA and sodium sulfinates to synthesize 3-sulfonylmethyl imidazo[1,2-α]pyridines (Figure 1).

2. Results and Discussion

The optimization of reaction conditions was carried out by using 2-phenylimidazo[1,2-α]pyridine (1a) as the model substrate, sodium p-toluenesulfinate (2a) as the sulfonylation reagent and DMA as the carbon synthon. During the early stages of this work, we mainly focused on different metal catalysts using K2S2O8 as an oxidant. The results showed that both K2S2O8 and the catalyst were essential for the transformation (Table 1, entries 1–3). Among the metal catalysts screened, including FeCl3, FeCl2, Fe3O4, CuI, Cu(acac)2, V(acac)2 and AgNO3, the best conversion with a 73% yield was obtained by FeCl3 in the DMA and H2O (2:1) hybrid solvent (Table 1, entries 4–10). As for the FeCl3 catalyst, 10 mol% loading was effective enough to give the highest productivity of 73% product. Reducing to 5 mol% FeCl3 gave comparable yields (Table 1, entries 6, 11–13). No products were obtained when the K2S2O8 oxidant was changed to H2O2, TBHP, O2 or I2O5 (Table 1, entries 14–17). The amount of K2S2O8 added was also shown to have some effects on the yields, and 2.5 eq. was optimal (Table 1, entries 6, 18–20).
Further screening demonstrated that H2O is vitally important, probably due to the fact that the low solubility of sodium sulfinate in DMA would lead to insufficient sulfur–reactant participation in a reaction without water (Table 1, entries 21–25). The best ratio of DMA and H2O is 2:1. To our delight, when increasing the loading of 2a, up to 90% yield was achieved (Table 1, entries 26–28). Furthermore, the reaction gave better results at higher temperatures such as 120 °C (Table 1, entries 29–32). Screening of other typical carbon source reagents, including DMF, DMSO and TMEDA, showed that DMA was the best (Table 1, entries 33–35).
With the optimum condition in hand (Table 1, entry 31), we then evaluated the scope of structurally different sodium sulfinates with 2-phenylimidazo[1,2-α]pyridin (Table 2). As shown in Table 2, sodium sulfinates bearing electron-donating (4-Me, 3-Me, 4-iPr, 4-OMe) or electron-withdrawing (4-CF3, 4-F, 4-Cl, 2-Cl, 4-Br) groups at the ortho, meta, or para positions were all compatible, affording good to excellent yields (Table 2, 3a–3j). Moreover, sodium aromatic heterocyclic sulfinate also tolerated well (Table 2, 3k–3l). To our surprise, this protocol was also applicable to sodium alkyl sulfinate, giving the target compounds in good yields (Table 2, 3m–3n). Regrettably, no product was generated when sodium triflate and sodium difluoromethanesulfinate were used (Table 2, 3o–3p).
We next turned our attention to imidazo[1,2-α]pyridines substrates bearing different substituents (Table 3). To our delight, the reaction of sulfonylmethylation could be smoothly accomplished with 2-(4-bromophenyl)imidazo[1,2-α]pyridine under the standard conditions, offering compound 3qa–3qf in good yields. This protocol can be effectively applied to 2-phenylimidazo-[1,2-α]pyridine with electron-donating groups (2-Me, 3-Me, 4-OCH3) and electron-withdrawing groups (4-NO2, 4-F, 4-Cl) (Table 3, 3ra–3rf). Imidazo[1,2-α]pyridine substituted in the 6, 7, and 8 positions was also well tolerated (Table 3, 3sa–3se). It is worth mentioning that heterocyclic substrates were amenable to this protocol, affording the desired product with good yields (Table 3, 3ta–3ud). However, some substrates are not suitable for this protocol (Table 3, 3v–3y).
In order to investigate the mechanism of the reaction, control experiments were explored, and the results are illustrated in Figure 2. Nearly no product was detected when 3 eq. radical scavenger (2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or 2,2-diphenyl-1-picrylhydrazyl (DPPH)) was added to the reaction system (Figure 2A), suggesting that a radical pathway might be involved in this protocol. Isotopic labeling experiments clearly showed that DMF provided the carbon attached to the imidazo heterocyclic backbone (Figure 2B).
According to our control experiments and the previous literature [11], a plausible mechanism of the sulfonylmethylation of imidazo[1,2-α]pyridines with DMA and sodium sulfinates is illustrated (Figure 3). DMA was firstly oxidized to iminium B by FeCl3/K2S2O8, which then reacted with electron-rich imidazopyridine to form intermediate C by C-C coupling. The sulfonylation of C by sodium p-toluenesulfinate generated 2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3a).

3. Experimental Section

General Information. All reactions were performed in a 10 mL tube with magnetic stirring. The imidazo[1,2-α] pyridines and sodium sulfinates are commercially available. Unless otherwise stated, all commercially available reagents were used without further purification. High-resolution mass spectra (ESI) were obtained with the Waters Xevo G2-XS QTOF. 1H NMR, 13C NMR and 19F NMR spectra were recorded at ambient temperature on Bruker 300 M instruments. All spectra were referenced to CDCl3 (1H NMR δ 7.26 ppm and 13C NMR δ 77.00 ppm). Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, qd = quartet of doublets, m = multiplet), coupling constants (Hz) and integration.
Experimental Procedure. In a typical experiment, a 15 mL sealed tube was charged with imidazo[1,2-α]pyridine, (0.6 mmol), substituted sodium sulfinate (1.2 mmol), DMA (4 mL), H2O (2 mL), K2S2O8 (2.5 eq) and FeCl3 (10 mol%). The mixture was allowed to stir at 120 °C and was monitored by TLC until the reaction was complete. Saturated aqueous NaCl solution was added to the reaction mixture and the aqueous phase was further extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under a vacuum to give the crude product. The residue was purified by column chromatography on silica gel using ethyl acetate/n-hexane (1:1) as the eluent to provide the desired product.
2-Phenyl-3-(tosylmethyl)imidazo[1,2-α] pyridine (3a) [29]. White solid, 195 mg, 90% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J = 6.9 Hz, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.35–7.27 (m, 6H), 7.09 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 4.88 (s, 2H), 2.36 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.42, 146.00, 145.33, 134.22, 133.03, 129.84, 128.34, 128.23, 128.16, 128.14, 126.03, 124.98, 117.50, 112.92, 108.29, 52.69, 21.67.
2-Phenyl-3-((m-tolylsulfonyl)methyl)imidazo[1,2-α]pyridine (3b) [29]. White solid, 185 mg, 85% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.31 (td, J = 7.4, 6.8, 3.9 Hz, 9H), 7.23 (d, J = 7.6 Hz, 1H), 6.96 (td, J = 6.9, 1.2 Hz, 1H), 4.88 (s, 2H), 2.26 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.60, 146.02, 139.79, 137.35, 135.10, 132.97, 129.14, 128.53, 128.50, 128.34, 128.28, 126.14, 125.42, 124.99, 117.58, 113.03, 108.20, 52.76, 21.30.
2-Phenyl-3-((phenylsulfonyl)methyl)imidazo[1,2-α]pyridine (3c) [29]. White solid, 184 mg, 88% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.59–7.52 (m, 3H), 7.39–7.29 (m, 8H), 6.96 (td, J = 6.9, 1.2 Hz, 1H), 4.91 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.67, 146.04, 137.51, 134.26, 132.99, 129.28, 128.55, 128.28, 128.25, 128.19, 126.08, 124.96, 117.57, 112.97, 108.03, 52.74.
3-(((4-Isopropylphenyl)sulfonyl)methyl)-2-phenylimidazo [1,2-α]pyridine (3d) [29]. White solid, 215 mg, 92% yield, ethyl acetate/n-hexane (1:1), 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.35–7.26 (m, 6H), 7.18 (d, J = 8.3 Hz, 2H), 6.97–6.89 (m, 1H), 4.87 (s, 2H), 2.97–2.83 (p, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 155.95, 147.53, 145.99, 134.74, 133.05, 128.49, 128.39, 128.23, 128.20, 127.42, 126.01, 125.01, 117.50, 112.89, 108.31, 52.80, 34.26, 23.61.
3-(((4-Methoxyphenyl)sulfonyl)methyl)-2-phenylimidazo [1,2-α]pyridine (3e) [29]. White solid, 205 mg, 90% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.34–7.28 (m, 2H), 7.26–7.18 (m, 6H), 6.85 (td, J = 6.8, 1.2 Hz, 1H), 6.69–6.58 (m, 2H), 4.79 (s, 2H), 3.72 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 164.10, 147.20, 145.90, 132.99, 130.30, 128.37, 128.15, 128.10, 125.99, 124.92, 117.47, 114.34, 112.90, 108.47, 55.63, 52.68.
3-(((4-Fluorophenyl)sulfonyl)methyl)-2-phenylimidazo[1,2-α]pyridine (3f) [29]. White solid, 171 mg, 78% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 6.9 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.29–7.23 (m, 5H), 7.22–7.10 (m, 5H), 6.92 (td, J = 6.9, 1.2 Hz, 1H), 4.87 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 167.79, 164.38, 147.38, 146.08, 132.95, 131.07, 130.93, 128.52, 128.26, 128.06, 126.11, 124.84, 117.60, 116.57, 116.27, 112.99, 107.91, 52.35. 19F NMR (282 MHz, CDCl3) δ-102.63.
3-(((4-Chlorophenyl)sulfonyl)methyl)-2-phenylimidazo[1,2-α]pyridine (3g) [29]. White solid, 183 mg, 80% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 6.8 Hz, 1H), 7.77–7.67 (m, 1H), 7.40–7.28 (m, 6H), 7.25 (s, 2H), 7.21–7.14 (m, 2H), 6.97 (d, J = 6.8 Hz, 1H), 4.93 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.06, 145.93, 141.27, 135.26, 132.50, 129.60, 129.48, 128.66, 128.51, 128.14, 126.61, 124.95, 117.60, 113.40, 107.98, 52.27.
3-(((2-Chlorophenyl)sulfonyl)methyl)-2-phenylimidazo[1,2-α]pyridine (3h) [29]. White solid, 170 mg, 74% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 7.0 Hz, 1H), 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 3.8 Hz, 3H), 7.35–7.27 (m, 5H), 7.24 (dd, J = 7.9, 1.2 Hz, 1H), 6.95 (td, J = 6.9, 1.2 Hz, 1H), 5.14 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 148.07, 146.22, 135.41, 135.27, 133.08, 132.91, 132.04, 132.01, 128.67, 128.52, 128.41, 127.37, 126.24, 125.10, 117.59, 113.07, 107.48, 50.37.
3-(((4-Bromophenyl)sulfonyl)methyl)-2-phenylimidazo[1,2-α]pyridine (3i) [29]. White solid, 210 mg, 82% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 6.9 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.31 (ddd, J = 7.8, 4.0, 2.3 Hz, 6H), 7.26–7.15 (m, 4H), 6.93 (td, J = 6.8, 1.2 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.37, 146.11, 135.75, 132.77, 132.36, 129.91, 129.56, 128.57, 128.32, 128.06, 126.26, 124.84, 117.63, 113.13, 107.82, 52.17.
2-Phenyl-3-(((4-(trifluoromethyl)phenyl)sulfonyl)methyl) imidazo[1,2-α]pyridine (3j). White solid, 188 mg, 75% yield. ethyl acetate/n-hexane (1:1), mp. 120–121 °C. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 6.9 Hz, 1H), 7.66–7.60 (m, 1H), 7.40 (d, J = 1.0 Hz, 4H), 7.33–7.26 (m, 1H), 7.21–7.12 (m, 5H), 6.92 (d, J = 6.1 Hz, 1H), 4.93 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.45, 146.20, 140.44, 132.74, 128.76, 128.68, 128.32, 127.92, 126.30, 126.11, 126.06, 124.82, 121.18, 117.70, 113.15, 107.42, 51.93. HRMS (ESI) m/z: [M + H]+ Calcd for C21H16F3N2O2S+ 417.0880, Found 417.0881.
2-Phenyl-3-((thiophen-2-ylsulfonyl)methyl)imidazo [1,2-α] pyridine (3k) [29]. White solid 166 mg, 78% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.57 (dd, J = 5.0, 1.3 Hz, 1H), 7.45–7.37 (m, 2H), 7.37–7.27 (m, 5H), 6.98–6.90 (m, 2H), 4.99 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.91, 146.12, 138.00, 135.41, 135.07, 132.98, 128.65, 128.41, 128.35, 128.21, 126.24, 124.95, 117.63, 113.12, 108.11, 54.07.
2-Phenyl-3-((pyridin-2-ylsulfonyl)methyl)imidazo[1,2-α] pyridine (3l) [29]. White solid, 146 mg, 70% yield, ethyl acetate/n-hexane (1:1), mp. 108–109 °C. 1H NMR (300 MHz, CDCl3) δ 8.60–8.54 (m, 1H), 8.45 (dt, J = 4.6, 1.4 Hz, 1H), 7.90–7.78 (m, 3H), 7.67–7.60 (m, 2H), 7.48–7.35 (m, 5H), 7.05 (t, J = 6.9 Hz, 1H), 5.23 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 156.10, 150.38, 147.67, 146.20, 137.96, 133.05, 128.72, 128.59, 128.37, 127.81, 126.25, 125.00, 122.90, 117.57, 113.07, 107.15, 48.81.
3-((Cyclopropylsulfonyl)methyl)-2-phenylimidazo[1,2-α] pyridine (3m) [29]. White solid, 149 mg, 80% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 7.0 Hz, 1H), 7.79 (dd, J = 8.2, 1.4 Hz, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.52–7.38 (m, 3H), 7.36–7.28 (m, 1H), 6.93 (dd, J = 6.9, 1.1 Hz, 1H), 4.86 (s, 2H), 2.12 (ddd, J = 12.8, 8.0, 4.8 Hz, 1H), 1.00 (dd, J = 4.7, 2.1 Hz, 2H), 0.68 (dd, J = 7.9, 2.2 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.08, 145.99, 133.51, 129.00, 128.64, 128.53, 126.21, 124.91, 117.52, 113.08, 108.12, 49.91, 28.80, 4.98.
3-((Methylsulfonyl)methyl)-2-phenylimidazo[1,2-α]pyridine (3n) [29]. White solid, 141 mg, 82% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 6.9 Hz, 1H), 7.75 (d, J = 6.8 Hz, 2H), 7.70 (d, J = 9.1 Hz, 1H), 7.54–7.47 (m, 2H), 7.47–7.41 (m, 1H), 7.36–7.30 (m, 1H), 6.94 (td, J = 6.9, 1.2 Hz, 1H), 4.83 (s, 2H), 2.63 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.44, 146.46, 133.54, 129.29, 128.87, 128.53, 126.30, 124.94, 117.82, 113.19, 108.02, 50.95, 39.61.
2-(4-Bromophenyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3qa) [29]. White solid, 221 mg, 84% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.45–7.38 (m, 4H), 7.37–7.31 (m, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 6.95 (td, J = 6.9, 1.2 Hz, 1H), 4.82 (s, 2H), 2.38 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.09, 146.06, 145.65, 134.35, 132.05, 131.55, 129.95, 129.78, 128.25, 126.39, 124.93, 122.53, 117.58, 113.20, 108.48, 52.64, 21.76.
2-(4-Bromophenyl)-3-(((4-methoxyphenyl)sulfonyl)methyl) imidazo[1,2-α]pyridine (3qb). White solid, 243 mg, 89% yield, ethyl acetate/n-hexane (1:1), mp. 230–231 °C. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 7.0 Hz, 1H), 7.67–7.61 (m, 1H), 7.39 (dd, J = 8.7, 3.7 Hz, 4H), 7.34–7.28 (m, 1H), 7.26–7.17 (m, 2H), 6.92 (td, J = 6.8, 1.2 Hz, 1H), 6.73 (d, J = 8.9 Hz, 2H), 4.82 (s, 2H), 3.82 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 164.33, 146.09, 146.03, 132.19, 131.58, 130.43, 129.76, 128.38, 126.31, 124.93, 122.45, 117.61, 114.44, 113.16, 108.69, 55.82, 52.65. HRMS (ESI) m/z: [M + H]+ Calcd for C21H18BrN2O3S+ 457.0216, Found 457.0217.
2-(4-Bromophenyl)-3-((phenylsulfonyl)methyl) imidazo[1,2-α]pyridine (3qc). White solid, 209 mg, 82% yield, ethyl acetate/n-hexane (1:1), mp. 213–214 °C. 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.52 (td, J = 7.0, 1.4 Hz, 3H), 7.34 (qd, J = 7.5, 6.7, 2.0 Hz, 4H), 7.23–7.12 (m, 3H), 6.89 (d, J = 6.9 Hz, 1H), 4.77 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.50, 146.15, 137.58, 134.47, 132.03, 131.76, 129.85, 129.45, 128.28, 126.42, 124.93, 122.70, 117.64, 113.24, 108.17, 52.76. HRMS (ESI) m/z: [M + H]+ Calcd for C20H16BrN2O2S+ 427.0111, Found 427.0111.
2-(4-Bromophenyl)-3-(((2-chlorophenyl)sulfonyl)methyl) imidazo[1,2-α]pyridine (3qd). White solid, 193 mg, 70% yield, ethyl acetate/n-hexane (1:1), mp. 227–228 °C. 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J = 6.9 Hz, 1H), 7.80 (dd, J = 8.1, 1.6 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.52–7.40 (m, 5H), 7.40–7.31 (m, 3H), 7.01 (td, J = 6.9, 1.2 Hz, 1H), 5.11 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.81, 146.27, 135.59, 135.46, 133.08, 132.15, 132.08, 131.86, 130.11, 127.54, 126.62, 125.10, 122.90, 117.64, 113.38, 107.61, 50.35. HRMS (ESI) m/z: [M–H]– Calcd for C20H13BrClN2O2S− 458.9569, Found 458.9570.
2-(4-Bromophenyl)-3-(((4-bromophenyl)sulfonyl)methyl) imidazo[1,2-α]pyridine (3qe). White solid, 228 mg, 75% yield, ethyl acetate/n-hexane (1:1), mp. 244–245 °C. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 7.0 Hz, 1H), 7.70–7.66 (m, 1H), 7.50–7.44 (m, 2H), 7.44–7.38 (m, 2H), 7.38–7.32 (m, 1H), 7.30–7.26 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.98 (td, J = 6.9, 1.2 Hz, 1H), 4.88 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.18, 135.92, 132.53, 131.81, 130.24, 129.69, 129.65, 126.63, 124.84, 122.81, 117.74, 113.44, 107.98, 52.27. HRMS (ESI) m/z: [M + H]+ Calcd for C20H15Br2N2O2S+ 506.9195, Found 506.9196.
2-(4-Bromophenyl)-3-((cyclopropylsulfonyl)methyl) imidazo[1,2-α]pyridine (3qf). White solid, 173 mg, 74% yield, ethyl acetate/n-hexane (1:1), mp. 204–205 °C. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 7.0 Hz, 1H), 7.74–7.64 (m, 3H), 7.64–7.57 (m, 2H), 7.35–7.28 (m, 1H), 6.93 (td, J = 6.9, 1.2 Hz, 1H), 4.80 (s, 2H), 2.24–2.17 (m, 1H), 1.08 (dt, J = 6.6, 3.3 Hz, 2H), 0.81 (tt, J = 8.0, 3.6 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.19, 146.09, 132.56, 132.11, 130.06, 126.32, 124.87, 122.94, 117.58, 113.17, 108.01, 50.00, 29.11, 5.12. HRMS (ESI) m/z: [M + H]+ Calcd for C17H16BrN2O2S+ 391.0110, Found 391.0111.
2-(o-Tolyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3ra) [29]. White solid, 185 mg, 82%, ethyl acetate/n-hexane (1:1), mp.133–134 °C. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.22 (dd, J = 9.0, 7.1 Hz, 3H), 7.12 (td, J = 7.5, 1.4 Hz, 1H), 7.02 (d, J = 7.6 Hz, 3H), 6.94 (t, J = 7.3 Hz, 1H), 6.86 (td, J = 6.9, 1.2 Hz, 1H), 6.62 (dd, J = 7.5, 1.3 Hz, 1H), 4.64 (s, 2H), 2.31 (s, 3H), 1.91 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.69, 145.66, 145.06, 137.38, 134.49, 131.82, 130.30, 129.87, 128.43, 128.05, 125.82, 125.29, 125.15, 117.48, 112.86, 109.31, 52.29, 21.67, 20.00.
2-(m-Tolyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3rb) [29]. White solid, 199 mg, 88% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 6.9 Hz, 1H), 7.59 (dd, J = 9.1, 1.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.25–7.20 (m, 1H), 7.09 (d, J = 1.3 Hz, 1H), 7.02 (d, J = 9.1 Hz, 5H), 6.84 (td, J = 6.9, 1.2 Hz, 1H), 4.79 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.50, 145.92, 145.26, 138.09, 134.39, 132.84, 129.84, 128.95, 128.26, 128.21, 126.06, 125.22, 125.04, 117.46, 112.93, 108.27, 52.81, 21.70, 21.47.
2-(4-Methoxyphenyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3rc) [29]. White solid, 212 mg, 90% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.24–7.18 (m, 3H), 7.03 (d, J = 7.8 Hz, 2H), 6.81 (td, J = 6.9, 1.2 Hz, 1H), 6.76–6.68 (m, 2H), 4.75 (s, 2H), 3.74 (s, 3H), 2.28 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 159.64, 147.23, 145.81, 145.27, 134.46, 129.80, 129.44, 128.16, 125.88, 125.46, 124.80, 117.24, 113.75, 112.75, 107.63, 55.31, 52.86, 21.63.
2-(4-Fluorophenyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3rd) [29]. White solid, 189 mg, 83% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 7.0 Hz, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.29–7.20 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H), 6.94–6.80 (m, 3H), 4.74 (s, 2H), 2.33–2.26 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 164.54, 161.25, 146.39, 145.94, 145.59, 134.49, 130.18, 130.07, 129.99, 129.21, 129.16, 128.28, 126.40, 125.04, 117.47, 115.59, 115.31, 113.18, 108.29, 52.74, 21.75.
2-(4-Chlorophenyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3re) [29]. White solid, 202 mg, 85% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.26–7.16 (m, 5H), 7.04 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 4.75 (s, 2H), 2.30 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 210.22, 146.05, 146.00, 145.62, 134.36, 134.30, 131.55, 129.94, 129.50, 128.59, 128.24, 126.39, 124.93, 117.53, 113.19, 108.46, 52.64, 21.72.
2-(4-Nitrophenyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3rf). White solid, 183 mg, 75% yield, ethyl acetate/n-hexane (1:1), mp.133–134 °C. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 7.0 Hz, 1H), 8.23–8.11 (m, 2H), 7.74 (d, J = 9.1 Hz, 1H), 7.69–7.63 (m, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.43–7.37 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.01 (td, J = 6.9, 1.1 Hz, 1H), 4.85 (s, 2H), 2.38 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.47, 146.35, 145.95, 144.83, 139.70, 134.42, 130.14, 128.98, 128.33, 126.97, 125.02, 123.68, 117.89, 113.69, 109.65, 52.69, 21.74. HRMS (ESI) m/z: [M + H]+ Calcd for C21H18N3O4S+ 408.1013, Found 408.1013.
8-Methyl-2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3sa) [29]. White solid, 201 mg, 93% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 6.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.20 (dt, J = 9.6, 2.8 Hz, 5H), 7.00 (d, J = 7.9 Hz, 3H), 6.74 (t, J = 6.9 Hz, 1H), 4.75 (s, 2H), 2.56 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.96, 146.32, 145.22, 134.42, 133.25, 129.83, 128.44, 128.31, 128.19, 127.99, 127.44, 124.82, 122.74, 112.91, 108.61, 52.85, 21.68, 17.18.
7-Methyl-2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3sb) [29]. White solid, 199 mg, 88% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 7.1 Hz, 1H), 7.34 (s, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.20–7.15 (m, 5H), 6.98 (d, J = 8.0 Hz, 2H), 6.67 (dd, J = 7.1, 1.6 Hz, 1H), 4.75 (s, 2H), 2.35 (d, J = 1.0 Hz, 3H), 2.26 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.02, 146.35, 145.25, 137.28, 134.16, 133.04, 129.79, 128.28, 128.15, 128.02, 124.20, 115.84, 115.56, 107.65, 52.69, 21.66, 21.44.
6-Methyl-2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3sc) [29]. White solid, 203 mg, 90% yield. ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.34–7.25 (m, 5H), 7.15 (dd, J = 9.2, 1.4 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 4.86 (s, 2H), 2.36 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.19, 145.32, 145.04, 134.35, 133.19, 129.85, 129.15, 128.33, 128.27, 128.20, 128.04, 122.69, 122.52, 116.86, 108.00, 52.81, 21.70, 18.55.
7-Chloro-2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3sd) [29]. White solid, 190 mg, 80% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.18 (s, 5H), 6.98 (d, J = 8.0 Hz, 2H), 6.89 (dd, J = 7.3, 2.0 Hz, 1H), 4.74 (s, 2H), 2.25 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.76, 145.92, 145.44, 133.98, 132.33, 129.85, 128.37, 128.13, 128.03, 125.44, 120.06, 119.50, 116.76, 108.83, 52.35, 21.65.
7-Bromo-2-phenyl-3-(tosylmethyl)imidazo[1,2-α]pyridine (3se). White solid, 211 mg, 80% yield, ethyl acetate/n-hexane (1:1). mp. 231–132 °C. 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.29–7.25 (m, 2H), 7.19 (s, 5H), 6.99 (d, J = 8.1 Hz, 2H), 6.79 (dd, J = 7.4, 2.1 Hz, 1H), 4.75 (s, 2H), 2.26 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.98, 145.65, 145.45, 134.01, 132.63, 132.41, 129.86, 128.37, 128.12, 128.05, 125.50, 116.17, 114.46, 108.75, 52.39, 21.64. HRMS (ESI) m/z: [M + H]+ Calcd for C21H18BrN2O2S+ 441.0267, Found 441.0267.
2-(Furan-2-yl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3ta) [29]. White solid, 173 mg, 82% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 8.2 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 7.0 Hz, 1H), 6.67 (d, J = 3.0 Hz, 1H), 6.35–6.24 (m, 1H), 5.07 (s, 2H), 2.26 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 148.92, 146.24, 145.13, 142.10, 137.51, 133.82, 129.22, 128.31, 126.45, 124.67, 117.09, 112.98, 111.08, 108.44, 107.95, 52.55, 21.50.
2-(t-Butyl)-3-(tosylmethyl)imidazo[1,2-α]pyridine (3tb).12 White solid, 176 mg, 86% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.76 (t, J = 6.9 Hz, 1H), 4.89 (s, 2H), 2.41 (s, 3H), 1.30 (d, J = 2.1 Hz, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ 155.80, 145.49, 144.90, 135.55, 130.04, 128.52, 125.27, 124.20, 116.92, 112.12, 106.12, 53.60, 34.18, 30.84, 21.68.
6-Phenyl-5-tosyl-2,3-dihydroimidazo[2,1-b]thiazole (3ua) [29]. White solid, 171 mg, 80% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 4.45 (s, 1H), 4.29 (t, J = 7.4 Hz, 1H), 3.78 (t, J = 7.3 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 151.08, 147.55, 145.20, 133.87, 133.20, 129.67, 128.06, 128.03, 127.10, 126.68, 113.96, 53.18, 46.11, 34.77, 21.55.
6-Phenyl-5-tosylimidazo[2,1-b]thiazole (3ub) [29]. White solid, 165 mg, 78% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 4.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.27–7.15 (m, 5H), 7.12 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 4.4 Hz, 1H), 4.69 (s, 2H), 2.34 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 150.77, 148.42, 145.37, 134.00, 133.01, 129.83, 128.27, 128.16, 127.78, 127.49, 119.07, 112.72, 109.77, 77.58, 77.16, 76.74, 53.45, 21.62.
2-(Thiophen-2-yl)-3-(tosylmethyl)imidazo[1,2-α] pyrimidine (3uc) [29]. White solid, 177 mg, 80% yield, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J = 6.7 Hz, 1H), 8.60 (s, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 3.2 Hz, 1H), 6.94 (s, 2H), 4.91 (s, 2H), 2.33 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 151.32, 148.80, 145.86, 142.92, 135.04, 134.03, 132.76, 130.04, 128.37, 127.58, 127.18, 126.24, 109.20, 106.21, 52.67, 21.71.
3-Methyl-1-phenyl-4-(tosylmethyl)-1H-pyrazol-5-amine (3ud) [34]. Yellow solid, 167 mg, yield 82%, ethyl acetate/n-hexane (1:1). 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.50–7.42 (m, 4H), 7.37–7.28 (m, 3H), 4.40 (br s, 2H), 4.12 (s, 2H), 2.43 (s, 3H), 1.62 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 148.75, 145.56, 144.99, 138.05, 134.66, 129.78, 129.58, 128.54, 127.61, 124.01, 90.17, 53.08, 21.65, 11.24.

4. Conclusions

In conclusion, we have developed a new sulfonylmethylation approach for imidazo[1,2-α]pyridines with DMA and sodium sulfinates affording diverse 3-(sulfonylmethyl)imidazo[1,2-α]pyridines in good yields with impressive simplicity. Free radical trapping and isotope labeling experiments showed that an oxidation-addition pathway might be included, and DMA provided carbon in this reaction.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29133196/s1, References [29,34] are cited in the supplementary materials.

Author Contributions

Conceptualization, X.B.; Methodology, S.S. and J.L.; Investigation, S.S. and H.Y.; Data curation, H.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study not involving humans or animals.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author/s.

Conflicts of Interest

There are no conflicts of interest to declare.

References

  1. Gladysz, R.; Adriaenssens, Y.; De Winter, H.; Joossens, J.; Lambeir, A.-M.; Augustyns, K.; Van der Veken, P. Discovery and SAR of novel and selective inhibitors of urokinase plasminogen activator (uPA) with an imidazo[1,2-α]pyridine scaffold. J. Med. Chem. 2015, 58, 9238–9257. [Google Scholar] [CrossRef] [PubMed]
  2. Kaminski, J.J.; Doweyko, A.M. Antiulcer agents. 6. Analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo [1,2-α] pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies. J. Med. Chem. 1997, 40, 427–436. [Google Scholar] [PubMed]
  3. Chen, X.; Xu, W.; Wang, K.; Mo, M.; Zhang, W.; Du, L.; Yuan, X.; Xu, Y.; Wang, Y.; Shen, J. Discovery of a novel series of imidazo[1,2-α]pyrimidine derivatives as potent and orally bioavailable lipoprotein-associated phospholipase A2 inhibitors. J. Med. Chem. 2015, 58, 8529–8541. [Google Scholar] [CrossRef] [PubMed]
  4. Hamdouchi, C.; Blas, J.D.; Prado, M.D.; Gruber, J.; Heinz, B.A.; Vance, L. 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl) vinyl] imidazo [1,2-α] pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity. J. Med. Chem. 1999, 42, 50–59. [Google Scholar] [CrossRef] [PubMed]
  5. Ramachandran, S.; Panda, M.; Mukherjee, K.; Choudhury, N.R.; Tantry, S.J.; Kedari, C.K.; Ramachandran, V.; Sharma, S.; Ramya, V.K.; Guptha, S.; et al. Synthesis and structure activity relationship of imidazo [1,2-α] pyridine-8-carboxamides as a novel antimycobacterial lead series. Bioorg. Med. Chem. Lett. 2013, 23, 4996–5001. [Google Scholar] [CrossRef] [PubMed]
  6. Baviskar, A.T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S.K.; Kundu, C.N.; Banerjee, U.C.; Bharatam, P.V. N-fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIα and induce apoptosis in G1/S phase. J. Med. Chem. 2011, 54, 5013–5030. [Google Scholar] [CrossRef] [PubMed]
  7. Bode, M.L.; Gravestock, D.; Moleele, S.S.; van der Westhuyzen, C.W.; Pelly, S.C.; Steenkamp, P.A.; Hoppe, H.C.; Khan, T.; Nkabinde, L.A. Imidazo [1,2-α] pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 2011, 19, 4227–4237. [Google Scholar] [CrossRef] [PubMed]
  8. Moraski, G.C.; Markley, L.D.; Cramer, J.; Hipskind, P.A.; Boshoff, H.; Bailey, M.A.; Alling, T.; Ollinger, J.; Parish, T.; Miller, M.J. Advancement of imidazo[1,2-α]pyridines with improved pharmacokinetics and nM activity vs. mycobacterium tuberculosis. ACS Med. Chem. Lett. 2013, 4, 675–679. [Google Scholar] [CrossRef] [PubMed]
  9. Koubachi, J.; El Kazzouli, S.; Bousmina, M.; Guillaumet, G. Functionalization of imidazo [1,2-α] pyridines by means of metal-catalyzed cross-coupling reactions. Eur. J. Org. Chem. 2014, 2014, 5119–5123. [Google Scholar] [CrossRef]
  10. Cao, H.; Zhan, H.; Lin, Y.; Lin, X.; Du, Z.; Jiang, H. Direct arylation of imidazo [1,2-α] pyridine at C-3 with aryl iodides, bro-mides, and triflates via copper (I)-catalyzed C–H bond functionali-zation. Org. Lett. 2012, 14, 1688–1692. [Google Scholar] [CrossRef]
  11. Fu, H.Y.; Chen, L.; Doucet, H. Phosphine-free palladium-catalyzed direct arylation of imidazo [1,2-α] pyridines with aryl bromides at low catalyst loading. J. Org. Chem. 2012, 77, 4473–4478. [Google Scholar] [CrossRef] [PubMed]
  12. Choy, P.Y.; Luk, K.C.; Wu, Y.; So, C.M.; Wang, L.-L.; Kwong, F.Y. Regioselective direct C-3 arylation of imidazo[1,2-α]pyridines with aryl tosylates and mesylates promoted by palladium-phosphine complexes. J. Org. Chem. 2015, 80, 1457–1463. [Google Scholar] [CrossRef] [PubMed]
  13. Firmansyah, D.; Deperasińska, I.; Vakuliuk, O.; Banasiewicz, M.; Tasior, M.; Makarewicz, A.; Cyrański, M.K.; Kozankiewicz, B.; Gryko, D.T. Double head-to-tail direct arylation as a viable strategy towards the synthesis of the aza-analog of dihydrocyclopenta [hi] aceanthrylene-an intriguing antiaromatic heterocycle. Chem. Commun. 2016, 52, 1262–1265. [Google Scholar] [CrossRef] [PubMed]
  14. Ghosh, M.; Naskar, A.; Mitra, S.; Hajra, A. Palladium-catalyzed α-selective alkenylation of imidazo[1,2-α]pyridines through aerobic cross-dehydrogenative coupling reaction. Eur. J. Org.Chem. 2015, 2015, 715–718. [Google Scholar] [CrossRef]
  15. Zhan, H.; Zhao, L.; Li, N.; Chen, L.; Liu, J.; Liao, J.; Cao, H. Ruthenium-catalyzed direct C-3 oxidative olefination of imidazo [1,2-α] pyridines. RSC Adv. 2014, 4, 32013–32016. [Google Scholar] [CrossRef]
  16. Cao, H.; Lei, S.; Liao, J.; Huang, J.; Qiu, H.; Chen, Q.; Qiu, S.; Chen, Y. Palladium (II)-catalyzed intermolecular oxidative C-3 alkenylations of imidazo [1,2-α] pyridines by substrate-contolled regioselective C-H functionalization. RSC Adv. 2014, 4, 50137–50140. [Google Scholar] [CrossRef]
  17. Monir, K.; Bagdi, A.K.; Ghosh, M.; Hajra, A. Regioselective oxidative trifluoromethylation of imidazoheterocycles via C(sp2)-H bond functionalization. J. Org. Chem. 2015, 80, 1332–1337. [Google Scholar] [CrossRef] [PubMed]
  18. Wu, A.; Zhang, H.-R.; Jin, R.-X.; Lan, Q.; Wang, X.-S. Nickel-catalyzed C-H trifluoromethylation of electron-rich heteroarenes. Adv. Synth. Catal. 2016, 358, 3528–3533. [Google Scholar] [CrossRef]
  19. Cao, H.; Lei, S.; Li, N.; Chen, L.; Liu, J.; Cai, H.; Qiu, S.; Tan, J. Cu-catalyzed selective C3-formylation of imidazo [1,2-α] pyridine C-H bonds with DMSO using molecular oxygen. Chem. Commun. 2015, 51, 1823–1825. [Google Scholar] [CrossRef]
  20. Mondal, S.; Samanta, S.; Jana, S.; Hajra, A. (Diacetoxy) iodobenzene-mediated oxidative C-H amination of imidazopyridines at ambient temperature. J. Org. Chem. 2017, 82, 4504–4510. [Google Scholar] [CrossRef]
  21. Lu, S.; Tian, L.-L.; Cui, T.-W.; Zhu, Y.-S.; Zhu, X.; Hao, X.-Q.; Song, M.-P. Copper-mediated C-H amination of imidazopyridines with N-fluorobenzenesulfonimide. J. Org. Chem. 2018, 83, 13991–14000. [Google Scholar] [CrossRef] [PubMed]
  22. Neto, J.S.S.; Balaguez, R.A.; Franco, M.S.; Machado, V.C.S.; Saba, S.; Rafique, J.; Galetto, F.Z.; Braga, A.L. Trihaloisocyanuric acids in ethanol: An eco-friendly system for the regioselective halogenation of imidazo-heteroarenes. Green Chem. 2020, 22, 3410–3415. [Google Scholar] [CrossRef]
  23. Semwal, R.; Ravi, C.; Kumar, R.; Meena, R.; Adimurthy, S. Sodium salts (NaI/NaBr/NaCl) for the halogenation of imidazo-fused heterocycles. J. Org. Chem. 2019, 84, 792–805. [Google Scholar] [CrossRef] [PubMed]
  24. Guo, T.; Wei, X.-N.; Zhang, M.; Liu, Y.; Zhu, L.-M.; Zhao, Y.-H. Catalyst and additive-free oxidative dual C-H sulfenylation of imidazoheterocycles with elemental sulfur using DMSO as a solvent and an oxidant. Chem. Commun. 2020, 56, 5751–5754. [Google Scholar] [CrossRef] [PubMed]
  25. Zhu, W.; Ding, Y.; Bian, Z.; Xie, P.; Xu, B.; Tang, Q.; Wu, W.; Zhou, A. One-pot three-component synthesis of alkylthio-/arylthio-substituted imidazo[1,2-α]pyridine derivatives via C(sp2)-H functionalization. Adv. Synth. Catal. 2017, 359, 2215–2221. [Google Scholar] [CrossRef]
  26. Hiebel, M.-A.; Berteina-Raboin, S. Iodine-catalyzed regioselective sulfenylation of imidazoheterocycles in PEG 400. Green Chem. 2015, 17, 937–944. [Google Scholar] [CrossRef]
  27. Lu, S.; Zhu, X.-J.; Li, K.; Guo, Y.-J.; Wang, M.-D.; Zhao, X.-M.; Hao, X.-Q.; Song, M.-P. Reactivity of p-toluenesulfonylmethyl isocyanide: Iron-involved C-H tosylmethylation of imidazopyridines in nontoxic media. J. Org. Chem. 2016, 81, 8370–8377. [Google Scholar] [CrossRef]
  28. Kalari, S.; Shinde, A.U.; Rode, H.B. Methylene-tethered arylsulfonation and benzotriazolation of aryl/heteroaryl C-H bonds with DMSO as a one-carbon surrogate. J. Org. Chem. 2021, 86, 17684–17695. [Google Scholar] [CrossRef] [PubMed]
  29. Chen, J.-W.; Wen, K.-M.; Wu, Y.-R.; Shi, J.; Yao, X.-G.; Tang, X.-D. Transition metal catalyst-free C-3 sulfonylmethylation of imidazo[1,2-α]pyridines with glyoxylic acid and sodium sulfinates in water. J. Org. Chem. 2022, 87, 3780–3787. [Google Scholar] [CrossRef]
  30. Lou, S.-J.; Xu, D.-Q.; Shen, D.-F.; Wang, Y.-F.; Liu, Y.-K.; Xu, Z.-Y. Highly efficient vinylaromatics generation via Iron-catalyzed sp3 C-H bond functionalization CDC reaction: A novel approach to preparing substituted benzo[α]phenazines. Chem. Commun. 2012, 48, 11993–11995. [Google Scholar] [CrossRef]
  31. Modi, A.; Ali, W.; Patela, B.K. N,N-dimethylacetamide (DMA) as a methylene synthon for regioselective linkage of imidazo[1,2-α]pyridine. Adv. Synth. Catal. 2016, 358, 2100–2107. [Google Scholar] [CrossRef]
  32. Kaswan, P.; Nandwana, N.K.; DeBoef, B.; Kumar, A. Vanadyl acetylacetonate catalyzed methylenation of imidazo[1,2-α]pyridines by using dimethylacetamide as a methylene source: Direct access to bis(imidazo[1,2-α]pyridin-3-yl)methanes. Adv. Synth. Catal. 2016, 358, 2108–2115. [Google Scholar] [CrossRef]
  33. Sun, S.-N.; Li, J.-C.; Gou, Y.-B.; Gao, Z.-H.; Bi, X.-J. Controllable synthesis of disulfides and thiosulfonates from sodium sulfinates mediated by hydroiodic acid using ethanol and H2O as solvents. Org. Biomol. Chem. 2022, 20, 8885–8892. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, J.-W.; Tian, J.-H.; Wen, K.-M.; Gao, Q.-W.; Shi, J.; Yao, X.-G.; Wu, T.; Tang, X.-D. A new method for C (sp2)-H sulfonylmethylation with glyoxylic acid and sodium sulfinates. Org. Biomol. Chem. 2022, 20, 1652–1655. [Google Scholar] [CrossRef]
Molecules 29 03196 g001
Figure 1. Comparison of recently reported sulfonylmethylation of imidazo[1,2-α]pyridines, refs. [27,28,29].
Figure 1. Comparison of recently reported sulfonylmethylation of imidazo[1,2-α]pyridines, refs. [27,28,29].
Molecules 29 03196 g001
Molecules 29 03196 g002
Figure 2. Control experiments. (A) Free radical trapping experiment; (B) Isotope labeling experiment.
Figure 2. Control experiments. (A) Free radical trapping experiment; (B) Isotope labeling experiment.
Molecules 29 03196 g002
Molecules 29 03196 g003
Figure 3. Proposed mechanism.
Figure 3. Proposed mechanism.
Molecules 29 03196 g003
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 03196 i001
EntryCatalyst/mol%Oxidant/EquivSolventYield/% b
1--DMA:H2O/2:10
2-K2S2O8/2.5DMA:H2O/2:15
3FeCl3/20-DMA:H2O/2:10
4CuI/20K2S2O8/2.5DMA:H2O/2:118
5Cu(acac)2/20K2S2O8/2.5DMA:H2O/2:118
6FeCl3/20K2S2O8/2.5DMA:H2O/2:173
7FeCl2/20K2S2O8/2.5DMA:H2O/2:167
8Fe3O4/20K2S2O8/2.5DMA:H2O/2:150
9V(acac)2/20K2S2O8/2.5DMA:H2O/2:163
10AgNO3/20K2S2O8/2.5DMA:H2O/2:16
11FeCl3/5K2S2O8/2.5DMA:H2O/2:141
12FeCl3/10K2S2O8/2.5DMA:H2O/2:173
13FeCl3/30K2S2O8/2.5DMA:H2O/2:170
14FeCl3/10H2O2/2.5DMA:H2O/2:10
15FeCl3/10TBHP/2.5DMA:H2O/2:10
16FeCl3/10O2/airDMA:H2O/2:10
17FeCl3/10I2O5/2.5DMA:H2O/2:10
18FeCl3/10K2S2O8/1.0DMA:H2O/2:157
19FeCl3/10K2S2O8/1.5DMA:H2O/2:164
20FeCl3/10K2S2O8/3.5DMA:H2O/2:173
21FeCl3/10K2S2O8/2.5DMA/10 eq 0
22FeCl3/10K2S2O8/2.5DMA/20 eq 0
23FeCl3/10K2S2O8/2.5DMA/50 eq 43
24FeCl3/10K2S2O8/2.5DMA:H2O/1:143
25FeCl3/10K2S2O8/2.5DMA:H2O/5:170
26 cFeCl3/10K2S2O8/2.5DMA:H2O/2:180
27 dFeCl3/10K2S2O8/2.5DMA:H2O/2:190
28 eFeCl3/10K2S2O8/2.5DMA:H2O/2:190
29 d,fFeCl3/10K2S2O8/2.5DMA:H2O/2:160
30 d,gFeCl3/10K2S2O8/2.5DMA:H2O/2:170
31 d,hFeCl3/10K2S2O8/2.5DMA:H2O/2:193
32 d,iFeCl3/10K2S2O8/2.5DMA:H2O/2:193
33 d,hFeCl3/10K2S2O8/2.5DMF:H2O/2:133
34 d,hFeCl3/10K2S2O8/2.5DMSO:H2O/2:10
35 d,hFeCl3/10K2S2O8/2.5TMEDA:H2O/2:10
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst, oxidant, solvent (2 mL), 110 °C, 4 h; b LC-MS; c 2a (1.5 eq); d 2a (2.0 eq); e 2a (2.5 eq); f 90 °C; g 100 °C; h 120 °C; i 130 °C.
Table 2. Substrate scope of sodium sulfinates a,b.
Table 2. Substrate scope of sodium sulfinates a,b.
Molecules 29 03196 i002
Molecules 29 03196 i003
a Reaction conditions: 1a (0.6 mmol), 2a (1.2 mmol), FeCl3 (10 mol%), K2S2O8 (2.5 eq), DMA:H2O = 2:1, 120 °C, 4 h; b isolated yields.
Table 3. Substrate scope of imidazo[1,2-α]pyridines a,b.
Table 3. Substrate scope of imidazo[1,2-α]pyridines a,b.
Molecules 29 03196 i004
Molecules 29 03196 i005
a Reaction conditions: 1a (0.6 mmol), 2a (1.2 mmol), FeCl3 (10 mol%), K2S2O8 (2.5 eq), DMA:H2O = 2:1, 120 °C, 8 h; b isolated yields.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Sun, S.; Ye, H.; Liu, H.; Li, J.; Bi, X. Iron-Catalyzed Sulfonylmethylation of Imidazo[1,2-α]pyridines with N,N-Dimethylacetamide and Sodium Sulfinates. Molecules 2024, 29, 3196. https://doi.org/10.3390/molecules29133196

AMA Style

Sun S, Ye H, Liu H, Li J, Bi X. Iron-Catalyzed Sulfonylmethylation of Imidazo[1,2-α]pyridines with N,N-Dimethylacetamide and Sodium Sulfinates. Molecules. 2024; 29(13):3196. https://doi.org/10.3390/molecules29133196

Chicago/Turabian Style

Sun, Shengnan, Hexia Ye, Haibo Liu, Junchen Li, and Xiaojing Bi. 2024. "Iron-Catalyzed Sulfonylmethylation of Imidazo[1,2-α]pyridines with N,N-Dimethylacetamide and Sodium Sulfinates" Molecules 29, no. 13: 3196. https://doi.org/10.3390/molecules29133196

APA Style

Sun, S., Ye, H., Liu, H., Li, J., & Bi, X. (2024). Iron-Catalyzed Sulfonylmethylation of Imidazo[1,2-α]pyridines with N,N-Dimethylacetamide and Sodium Sulfinates. Molecules, 29(13), 3196. https://doi.org/10.3390/molecules29133196

Article Metrics

Back to TopTop